In the years since Knowles and co-workers demonstrated that synthetic catalysts could approach the levels of absolute stereocontrol achieved by enzymes (B. D. Vineyard, W. S. Knowles, M. J. Sabacky, G. L. Bachman, D. J. Weinkauff, Asymmetric hydrogenation. Rhodium chiral bisphosphine catalyst, J. Am. Chem. Soc. 99, 5946 (1977)), chemists have made remarkable progress on the synthesis of optically active molecules using catalytic chiral inputs. Despite the advances, the subset of reactions that can be performed with enantioselective methods still represents only a fraction of the pool of known organic transformations. One reason for this discrepancy is that although new ligand designs and catalyst variants have been reported at a striking rate, a slower pace has been set for devising alternative underlying approaches to inducing asymmetry.
Among the distinct strategies that complement the traditional metal-chiral ligand methods, asymmetric phase-transfer catalysis has undoubtedly been one of the most successful. In this mode of catalysis, a lipophilic chiral cation salt mediates the reaction between a substrate in organic solution and an anionic reagent in a separate aqueous or solid phase. Ion-pairing with the cation solubilizes the anionic reagent or reaction intermediate in the bulk organic phase, while also providing a chiral environment for the desired reaction with the substrate. Application of this simple logic has yielded a diverse array of operationally simple, highly enantioselective protocols (K. Maruoka, Ed., Asymmetric Phase Transfer Catalysis (Wiley-VCH, Weinheim, Germany, 2008); M. J. O'Donnell, in Catalytic Asymmetric Synthesis, I. Ojima, Ed. (Wiley-VCH, New York, 2000), 2nd ed. chap. 10, pp. 727; T. Ooi, K. Maruoka, Recent advances in asymmetric phase-transfer catalysis, Angew. Chem. Int. Ed. 46, 4222 (2007); B. Lygo, B. I. Andrews, Asymmetric phase-transfer catalysis utilizing chiral quaternary ammonium salts: asymmetric alkylation of glycine imines, Acc. Chem. Res. 37, 518 (2004)).
However, almost no consideration has been given to an analogous charge-inverted strategy in which the salt of a chiral anion brings an insoluble cationic promoter into solution. This neglected other half of phase-transfer catalysis could be quite useful. An area of chemistry with broad utility in which charge-inverted phase-transfer catalysis play a role would be uniquely advantageous.
Procedures for the construction of carbon-fluorine bonds are highly prized due to the scarcity of methods and the value of the products across applied chemistry (I. Ojima, Ed., Fluorine in Medicinal Chemistry and Chemical Biology (Wiley-Blackwell, 2009); S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Fluorine in medicinal chemistry, Chem. Soc. Rev. 37, 320 (2008); T. Furuya, A. S. Kamlet, T. Ritter, Catalysis for fluorination and trifluoromethylation, Nature 473, 470 (2011); M. H. Katcher, A. Sha, A. G. Doyle, Palladium-catalyzed regio- and enantioselective fluorination of acyclic allylic halides, J. Am. Chem. Soc. 133, 15902 (2011)). Within the realm of drug design, the stereospecific incorporation of fluorine substituents is a powerful and widely employed tactic to circumvent metabolism issues arising from in vivo C—H bond oxidation. On this basis, the catalytic production of carbon-fluorine stereogenicity has become a methodological goal of central importance to practitioners of chemical and pharmaceutical synthesis. Surprisingly, however, catalytic methods for the asymmetric construction of C—F bonds are rare, the majority involving α-substituted β-keto ester substrates that are structurally precluded from product epimerization (see Hamashima et al. (2005) Tetrahedron Lett. 46:1447; Shibara et al. (2004) Synlett. 1703; Ma et al. (2004) Tetrahedron Asym. 1007; Kim (2002) Org. Lett. 4:545).
Electrophilic reagents have proven to be one of the most applicable vehicles for introducing fluorine into organic molecules (S. Stavber, Recent advances in the application of Selectfluor F-TEDA-BF4 as a versatile mediator or catalyst in organic synthesis, Molecules 16, 6432 (2011); J. Baudoux, D. Cahard, in Organic Reactions, S. E. Denmark, Ed. (Wiley, Hoboken, 2007), ch. 2, pp. 347-672; P. T. Nyffeler, S. G. Duron, M. D. Burkart, S. P. Vincent, C.-H. Wong, Selectfluor: Mechanistic insight and applications, Angew. Chem. Int. Ed. 44, 192 (2005); C. Bobbio, V. Gouverneur, Catalytic asymmetric fluorinations, Org. Biomol. Chem. 4, 2065 (2006); J.-A. Ma, D. Cahard, Asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions, Chem. Rev. 108, PR1 (2008); S. Lectard, Y. Hamashima, M. Sodeoka, Recent advances in catalytic enantioselective fluorination reactions, Adv. Synth. Catal. 352, 2708 (2010)). Unfortunately, the mechanism of these reactions offers little room for addition of a chiral catalyst. Many of the most effective published enantioselective fluorination protocols involve formation of a nucleophilic chiral enolate equivalent (L. Hintermann, A. Togni, Catalytic enantioselective fluorination of β-ketoesters, Angew. Chem. Int. Ed. 39, 4359 (2000); T. Suzuki, T. Goto, Y. Hamashima, M. Sodeoka, Enantioselective fluorination of tertbutoxycarbonyl lactones and lactams catalyzed by chiral Pd(II)-bisphosphine complexes, J. Org. Chem. 72, 246 (2007); Y. Hamashima, T. Suzuki, Y. Shimura, T. Shimizu, N. Umebayashi, T. Tamura, N. Sasamoto, M. Sodeoka, An efficient catalytic enantioselective fluorination of β-ketophosphonates using chiral palladium complexes, Tetrahedron Lett. 46, 1447 (2005); H. R. Kim, D. Y. Kim, Catalytic enantioselective fluorination of α-cyano acetate catalyzed by chiral palladium complexes, Tetrahedron Lett. 46, 3115 (2005); X. Wang, Q. Lan, S. Shirakawa, K. Maruoka, Chiral bifunctional phase transfer catalysts for asymmetric fluorination of β-keto esters, Chem. Commun. 46, 321 (2010); M. Marigo, D. Fielenbach, A. Braunton, A. Kjærsgaard, K. A. Jørgensen, Enantioselective formation of stereogenic carbon-fluorine centers by a simple catalytic method, Angew. Chem. Int. Ed. 44, 3703 (2005); D. D. Steiner, N. Mase, C. F. Barbas III, Direct asymmetric α-fluorination of aldehydes, Angew. Chem. Int. Ed. 44, 3706 (2005); T. D. Beeson, D. W. C. MacMillan, Enantioselective organocatalytic α-fluorination of aldehydes. J. Am. Chem. Soc. 127, 8826 (2005); P. Kwiatkowski, T. D. Beeson, J. C. Conrad, D. W. C. MacMillan, Enantioselective organocatalytic α-fluorination of cyclic ketones, J. Am. Chem. Soc. 133, 1738 (2011)), including one report of formation through chiral cationic phase transfer catalysis (X. Wang, Q. Lan, S. Shirakawa, K. Maruoka, Chiral bifunctional phase transfer catalysts for asymmetric fluorination of β-keto esters. Chem. Commun. 46, 321 (2010)). On the other hand, the catalytic generation of a chiral electrophile has proven quite challenging; usually a stoichiometric amount of chiral promoter is necessary to suppress the racemic background reaction (D. Cahard, C. Audouard, J.-C. Plaquevent, N. Rogues, Design, synthesis, and evaluation of a novel class of enantioselective electrophilic fluorinating reagents: N-fluoro ammonium salts of cinchona alkaloids (F-CA-BF4). Org. Lett. 2, 3699 (2000); N. Shibata, E. Suzuki, Y. Takeuchi, A fundamentally new approach to enantioselective fluorination based on cinchona alkaloid derivatives/Selectfluor combination, J. Am. Chem. Soc. 122, 10728 (2000); T. Ishimaru, N. Shibata, T. Horikawa, N. Yasuda, S. Nakamura, T. Toni, M. Shiro, Cinchona alkaloid catalyzed enantioselective fluorination of allyl silanes, silyl enol ethers, and oxindoles, Angew. Chem. Int. Ed. 47, 4157 (2008); O. Lozano, G. Blessley, T. Martinez del Campo, A. L. Thompson, G. T. Giuffredi, M. Bettati, M. Walker, R. Borman, V. Gouverneur, Organocatalyzed enantioselective fluorocyclizations, Angew. Chem. Int. Ed. 50, 8105 (2011)).
There is, accordingly, a need in the art for an improved enantioselective fluorination method. An ideal method would enable rapid and enantiocontrolled C—F bond formation using stable, inexpensive reagents and catalysts that are inert to product epimerization and readily allow the fluorinated compound to be further functionalized. The introduction of chiral anion phase-transfer catalysts of use in catalyzing electrophilic reactions, e.g., halogenation, and methods of using these catalysts would represent a significant advance in the art. The present invention provides such catalysts and methods for carrying out electrophilic addition reactions mediated by chiral anion phase-transfer catalysts.